The long-range objectives of this application are to utilize the unique aspects of osteoclast motility as targets in the rational design of pharmacologic agents for regulation of bone remodeling. The central hypothesis that is being tested is that the gelsolin-based signaling complex of the osteoclast podosome is unique and provides tissue specificity and sensitivity, making it an attractive pharmacologic target. In this proposal, the downstream targets of the gelsolin complex, in particular, the PI 3-kinase that produces a signaling phospholipid (PIP3) that is used for podosome organization in osteoclast activation, will be analyzed. The hypothesis is that critical cell survival signals are stimulated by PIP3 during osteoclast motility through activation of Akt. Furthermore, PTEN will be studied for its regulation of Akt and PIP3. In the second series of experiments, studies are proposed to analyze the function of a newly identified osteoclast-specific protein, leupaxin, which associates with the cytoskeleton and a member of the focal adhesion kinase family of proteins, PYK2. In the third Specific Aim, the applicant proposes to test the hypothesis that the Arp2/3 complex regulates the pointed end turnover of podosome actin filaments, working in conjunction with gelsolin to regulate podosome assembly and turnover. Studies in this proposal will be performed in avian and murine osteoclasts that are transduced by fusion proteins containing a human immunodeficiency virus peptide, TAT, which can transduce proteins across cell membranes.